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Prof. Natalie Ahn

Phosphorylation-regulated protein dynamics in kinase regulation and implications for inhibitor design: The case of ERK2

The MAP kinases, extracellular-regulated protein kinases 1 & 2 (ERK1/2), are important drug targets for cancers caused by oncogenic mutations in RAS and B-RAF. Preclinical studies show that cells from metastatic cancers with acquired resistance to RAF and MKK inhibitors can be effectively killed using small molecule inhibitors of ERK, some of which are in early stage clinical trials. An important unsolved question is: How is ERK2 activated by dual phosphorylation at Thr and Tyr residues, both catalyzed by MKK1/2? Using hydrogen exchange mass spectrometry and NMR relaxation dispersion experiments, we discovered that the activation of ERK2 involves the release of protein motions, leading to global exchange between conformational states which we believe function to enable productive nucleotide binding. An intriguing possibility is that these phosphorylation-regulated dynamics may be coupled to steps in catalytic turnover. Importantly, high affinity ERK inhibitors, which are effective towards cells with acquired resistance, show properties of conformation selection in a manner correlating with slow dissociation. Our findings suggest that the regulated dynamics of ERK2 are exploited by these inhibitors to improve their kinetic properties and efficacy.

The school is engaged in cutting edge research across the full breadth or modern chemistry and biochemistry. Our activities bridge traditional boundaries between scientific disciplines and involve partnerships across the campus, around the country and internationally. Research lies as the core of graduate education in the chemical and biochemical sciences, but there are also many opportunities for Georgia Tech undergraduates to work alongside our Ph.D. researchers and graduate students to develop their professional skills.

Members of our distinguished faculty are engaged in the education of ~350 Chemistry or Biochemistry undergraduate majors, ~240 Chemistry graduate students and more than 2,000 other undergraduates each year through their service teaching activities. The school’s extensive and internationally recognized research programs engage its graduate students, ~110 PhD researchers, many undergraduates and collaborators, throughout the campus and from around the world, in cutting edge science. These programs are supported by a highly talented administrative, technical and scientific staff.

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